Circadian Clock Disruption and Colorectal Cancer

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Despite the advantages of polyp screening for early detection, early-onset CRC incidence is on an alarming rise in young adults under the age of 50. Though the underlying cause of early-onset CRC remains fully undefined, suspected risk factors include behavior and lifestyle elements that govern systemic physiology and are under the control of the circadian clock. Strikingly, epidemiology evidence links deregulation of circadian rhythms through night shift work with multiple cancer types, including CRC. The circadian clock is the endogenous biological pacemaker which controls physiological, immune, endocrine, and metabolic processes that operate to maintain organismal homeostasis within a strict 24-hour period. Several lines of evidence suggest that deregulation of circadian rhythms results in cancer initiation and progression, yet the precise molecular mechanisms and detailed signaling pathways have yet to be elucidated. Moreover, in relation to CRC, the crosstalk between the circadian clock and proliferative, metabolic, and immune pathways in the intestine are not fully elucidated, and more specifically, how this crosstalk is involved in CRC progression remains unresolved. To address this knowledge gap, we have generated a genetically engineered mouse model (GEMM) to elucidate the effects of circadian clock disruption on the intestinal epithelium that drive CRC pathogenesis. Our central hypothesis is that disruption of the circadian clock aberrantly drives crucial signaling pathways that remodel the immune landscape, promote immunosuppression, and accelerate CRC. Aim 1 of this proposal will delineate the crosstalk between the circadian clock and crucial signaling pathways that regulation inflammation in the intestine. Aim 2 will define the underlying molecular mechanism of how the clock impinges on temporal control of tumor immunity. Aim 3 of this proposal will define how the circadian clock controls cellular metabolic pathways that could contribute to immunosuppression. Taken together, our studies have important clinical implications in understanding how disruption of the biological pacemaker, on the molecular level, alters tumor initiation and disease progression to accelerate CRC pathogenesis. These findings will provide novel insight and a molecular rationale for approaches underlying therapeutic targeting of the circadian clock for the treatment of CRC.